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Kicking out extra chromosomes

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A way to put right cells that contain the wrong numbers of chromosomes has been uncovered by UK scientists...

Normally, human cells contain 23 pairs of chromosomes, one of each pair coming from each of our parents. But, occasionally, something goes wrong and one or more extra copies can crop up in some or all of our cells. One situation where this happens quite often is with the sex chromosomes - these are the X and Y chromosomes you have if you're a man and the two X chromosomes you carry if you're a woman, and about one in 500 men has an extra X or Y chromosome in their cells. This can affect fertility by preventing healthy sperm production. Now James Turner, at the Crick Institute, in London, has potentially found a way to fix this and reset the chromosome copy number back to the right level.

The team were studying mice that mimic the Human condition by carrying an extra X or Y chromosome in their cells. Skin cells collected from the ear were re-programmed in the dish to convert them into an unspecialised state referred to as iPS or induced pluripotent stem cells. These they intended next to turn into sperm cells.

"But, serendipitiously, we found that a high fraction [30%] of these cells had lost the extra X or Y chromosome, so they were now normal - just XY," explains Turner.

The team were able to take these stem cells and, through further manipulation and ultimately implantation into an adult testis, turn them into sperm cells capable of fertilising eggs and producing healthy mouse pups with a normal chromosome count.

So can cells count, and is this how the stem cells were discarding the extra chromosome copies to set the genetic record straight? Turner doesn't think so. "Actually, we believe that something much more pedestrian is going on!" Instead he speculates that the genetic burden imposed by carrying additional chromosomal cargo disadvantages cells when they are being reprogrammed in the dish. This means that any cells that, by chance, shed their extra chromosomes gain a fitness advantage and grow faster, making them more common in the culture population.

"We do also see the same chromosome loss when we start with cells that have the correct number of chromosomes to begin with, just at a much lower frequency."

The repair effect is also not confined to disorders of sex chromosomes. Stem cells produced in the same way from mice engineered to carry instead extra copies of chromosome 21, which is duplicated in humans with Down's Syndrome, also shed the extra chromosome in about 50% of cases. The experiments were designed in order to probe where during the process this occurs and showed that the reprogramming event, back to an iPS cell type, is the most likely point.

The exciting spin off from the discovery, which is published this week in Science, is that it could be used to assist individuals with infertility caused by additional copies of chromosomes. "But that's a long way off," cautions Turner. "Turning reprogrammed stem cells into sperm cells is long and complicated. It also involves transplanting the cells back into a mature testis to complete their maturation into sperm cells, and some of the animals in which we do this develop tumours. So there's a long way to go before this is safe for a human."